The proposed work aims to develop sensitive non-invasive methods to detect, characterize and quantify lung injury in chronic obstructive pulmonary disease (COPD). Such methods may aid in the early detection of COPD, the study of its pathogenesis, and the evaluation of strategies for prevention and therapy. Specifically, we will investigate aerosol methods of detecting lung injury in an animal model of emphysema. These methods analyze the deposition and washout of inspired aerosol boluses to provide indices of: 1) airspace enlargement, and 2) disease-induced nonuniform ventilation. Preliminary data indicates that these methods are more sensitive and specific to mild lung injury than standard tests of lung function which are currently available. We hypothesize that: 1) Aerosol tests can detect and quantify airspace enlargement and its nonuniform distribution in emphysema, 2) Aerosol tests can detect and characterize disturbances to convective flow caused by mild or early lung injury, 3) Aerosol tests, combined with tests of lung mechanics can elucidate the sequence and relationship of four distinct consequences of lung injury in emphysema: airspace enlargement, loss of elastic recoil, airflow obstruction, and uneven ventilation. These hypotheses will be tested by inducing emphysema in dogs by exposing their lungs to a proteolytic enzyme (papain) with the dose chosen to simulate early or mild disease. Aerosol measurements will be performed longitudinally during a 12-week period post exposure. Lung injury will be confirmed and characterized, in-vivo, by measurements of lung volumes, lung compliance, forced expiratory flows, diffusing capacity, inert gas washouts, and gamma scintigraphy. At the end of the experiments, morphometric analysis of lung tissue will be used to characterize parenchymal and bronchiolar disease. In some studies, periodic computed tomography will serve as an additional measure of emphysematous changes.